PROJECT SUMMARY/ABSTRACT The Prostate Cancer Program (PCaP) consists of 50 members (30 primary, 18 associate, 2 adjunct) from 16 departments. The program is led by Dr. Christopher J. Logothetis, an internationally recognized medical oncologist, and co-led by Drs. Timothy C. Thompson, a laboratory scientist, and Filippo Giancotti, an accomplished physician-scientist. The major scientific goal of the PCaP is to build on our understanding of prostate cancer to develop more effective treatment and improve standard of care. The program is organized around 3 themes: 1) Biomarkers for Progression and Prediction; 2) Targeting the Immune and Non-immune Components of the Microenvironment, including the immune component; and 3) Targeting Cancer Cell Signaling. Each theme is addressed by a specific aim. Aim 1: To develop new tests from blood, urine, and tumor tissues that predict tumor recurrence, progression, and sensitivity or resistance to existing and novel therapies. Aim 2: To understand tumor cell-host interactions and translate this knowledge into the development of novel therapeutic approaches targeting the microenvironment. Aim 3: To target prostate cancer cell signaling with novel single agents and with combinations of agents used sequentially or concurrently. The annual direct peer- reviewed funding totals $3,693,347, including a Prostate Cancer SPORE, and $2,204,086 (60%) is from NCI grants. Since the last submission, the program has authored 350 published papers, of which 183 (52%) are intra- programmatic, 112 (32%) are inter-programmatic, and 245 (70%) are external collaborations. Forty-nine percent of publications appeared in journals with IF >5 and 23% appeared in journals with IF >10, including Cancer Cell, Lancet Oncol, Proc Natl Acad Sci USA, Nature, N Engl J Med, Cell, Nat Genet, J Natl Cancer Inst, Sci Transl Med, and J Clin Oncol. Program members use all 14 shared resources. Over the past 6 years, the PCaP has 1) discovered biomarkers that predict responsiveness or initial/acquired resistance to the second-generation androgen receptor signaling inhibitors; 2) identified biomarkers associated with the ?aggressive variant? prostate cancer phenotype that predict response to platinum-based combinations in clinical and co-clinical models; 3) discovered immunotherapy targets in prostate cancer (e.g., VISTA) that are expressed on T cells and antigen- presenting cells, including macrophages; 4) linked myeloid-derived suppressor cells with immune checkpoint blockade resistance in prostate cancer; 5) identified FGF as a target in prostate cancer, providing a mechanism of action for the VEGFR and c-met inhibitor cabozantinib; 6) elucidated the impact of cross-talk between PI3K/AKT/mTOR signaling in regulating efficacy of targeted therapy for prostate cancer; 7) identified prostate cancer vulnerability to PARP inhibitors regulated by androgen inhibitor-mediated BRCAness; and 8) identified cancer-induced transition of endothelial cells to cells with osteoblastic function and associated them with bone metastases.